Early Identification and Prevention of

Fetal Alcohol Spectrum Disorders: the

NIAAA Collaborative Initiative in Eastern

Europe

Early Identification and Prevention of

Fetal Alcohol Spectrum Disorders: the

NIAAA Collaborative Initiative in Eastern

Europe

Christina Chambers, PhD, MPH

Pediatrics and Family and Preventive Medicine

University of California San Diego

La Jolla, CA, USA

Christina Chambers, PhD, MPH

Pediatrics and Family and Preventive Medicine

University of California San Diego

La Jolla, CA, USA

Collaborative Initiative on Fetal

Alcohol Spectrum Disorders

(CIFASD)

Collaborative Initiative on Fetal

Alcohol Spectrum Disorders

(CIFASD)

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Under-recognition of FAS/DUnder-recognition of FAS/D

� Difficulty in making the diagnosis, especially in the newborn period

� Lack of expertise among general pediatricians, or poor access to expert diagnostic teams to achieve consistent validity of diagnoses

� Lack of a clearly defined/distinct neurobehavioral phenotype

� Poor ascertainment of alcohol use by pregnant women

– Stoler JM et al J Pediatr 135:430-6 (1999)

– Elliott EJ et al J Paediatr Child Health 42:698-703 (2006)

– Elgen I et al Acta Pediatrica 96:237-41 (2007)

� Difficulty in making the diagnosis, especially in the newborn period

� Lack of expertise among general pediatricians, or poor access to expert diagnostic teams to achieve consistent validity of diagnoses

� Lack of a clearly defined/distinct neurobehavioral phenotype

� Poor ascertainment of alcohol use by pregnant women

– Stoler JM et al J Pediatr 135:430-6 (1999)

– Elliott EJ et al J Paediatr Child Health 42:698-703 (2006)

– Elgen I et al Acta Pediatrica 96:237-41 (2007)

Other unanswered questionsOther unanswered questions

� How much alcohol, when and in what pattern presents a risk?

� What factors (e.g., genetic susceptibility, nutritional factors, other exposures) increase or decrease that risk for FASD, and can we intervene to prevent or ameliorate the disorder during pregnancy?

� What methods can be used to provide earlier identification of affected children in support of earlier intervention and treatment?

� How much alcohol, when and in what pattern presents a risk?

� What factors (e.g., genetic susceptibility, nutritional factors, other exposures) increase or decrease that risk for FASD, and can we intervene to prevent or ameliorate the disorder during pregnancy?

� What methods can be used to provide earlier identification of affected children in support of earlier intervention and treatment?

Informatics

Stewart

Dysmorphology

Jones

AdministrativeRiley

Hull Thomas

Foroud

SowellM

att

son

Cham

bers

New

Sulik

Cudd

Zh

ou

New

Collaborative Initiative on Fetal AlcoholSpectrum Disorders (CIFASD)

Integration and translation among CIFASD

projects

Integration and translation among CIFASD

projects

C. ChambersAssessment of

Neonates

K. JonesDysmorphology

Core

S. MattsonBehavioral Phenotypes

E. SowellBrain Imaging

T. Foroud3D FacialImaging

Establishing

Standardized

Criteria

F. ZhouMouse Model

K. SulikMouse MRI

A. HullPrenatal

Ultrasound

T. CuddSheep Model

C. StewartInformatics

E. RileyAdmin

South AfricaSouth Africa

The diagnostic and research team in S.A., 1999

Prevalence of Fetal Alcohol Syndrome Western

Cape Province, South Africa - Wave 3

Prevalence of Fetal Alcohol Syndrome Western

Cape Province, South Africa - Wave 3

68.0 - 89.2/1,000Rate

55 FAS+18 FASDFinal diagnosis

30 FAS+78 DeferredPreliminary diagnosis

244 + 62Dysmorphology exam (Tier 2)

818Screened for growth (Tier 1)

1,013Total in 1st grade

Number of ChildrenCategory

May PA et al Drug and Alcohol Dependence 88:259-71 (2007)

ItalyItaly

Prevalence of Fetal Alcohol SyndromeLazio Province, Italy

Prevalence of Fetal Alcohol SyndromeLazio Province, Italy

3.7 - 7.4 per 1,000 FAS

20.3 - 40.5 per 1,000 FASD

Rates

4 FAS + 17 FASD + 1 ARNDFinal diagnosis

230Total dysmorphology exam

(Tier 2)

543Total evaluated (Tier 1)

1,086Total N in 1st grade

Number of ChildrenCategory

May PA Alcoholism Clin Exp Res 30:1562-75 (2006)

RussiaRussia

Fetal Alcohol Syndrome in Boarding Schools and Orphanages in Moscow

Fetal Alcohol Syndrome in Boarding Schools and Orphanages in Moscow

17 (8.9%)17190 (76%)218Orphanages for

Normal or Mildly

Delayed Children

N = 3

69 (12.3%)71561 (87%)648Orphanages for

Children with

Mental Deficiency

N = 7

27 (6.1%)35574 (76%)760Boarding Schools

for Children Mental

Deficiency

N = 5

Confirmed

Diagnosis

FAS

Preliminary

Diagnosis

FASChildren

Examined

Total

Number

ChildrenFacility

Marintcheva G et al Soc Clin Psychiatry 3:17-22 (2003)

Russia/Ukraine CIFASD Clinical ProjectRussia/Ukraine CIFASD Clinical Project

� Prospective cohort study involving moderate to heavily exposed pregnant women screened during routine prenatal

care and low/unexposed comparison women

� Prospective cohort study involving moderate to heavily exposed pregnant women screened during routine prenatal

care and low/unexposed comparison women

Investigators/CollaboratorsInvestigators/Collaborators

� Christina Chambers - UCSD

� Ken Jones - UCSD

� Claire Coles - Emory University

� Julie Kable - Emory University

� Carl Keen - UC Davis

� Jan Uriu-Adams - UC Davis

� Andrew Hull - UCSD

� Ludmila Bakhireva - UNM

� Lily Xu - UCSD

� Christina Chambers - UCSD

� Ken Jones - UCSD

� Claire Coles - Emory University

� Julie Kable - Emory University

� Carl Keen - UC Davis

� Jan Uriu-Adams - UC Davis

� Andrew Hull - UCSD

� Ludmila Bakhireva - UNM

� Lily Xu - UCSD

� Lyubov Yevtushok - Omni Net -Rivne, Ukraine

� Wladimir Wertelecki - U. So. Alabama

� Lela Kavteladze - Moscow Regional Institute of OB/Gyn

� Ludmila Joutchenko - Moscow Regional Genetics

� Anatoly Skalny - Center for Biotech Medicine, Moscow

� Pavel Ogurtsov -Friendship University, Moscow

� Lyubov Yevtushok - Omni Net -Rivne, Ukraine

� Wladimir Wertelecki - U. So. Alabama

� Lela Kavteladze - Moscow Regional Institute of OB/Gyn

� Ludmila Joutchenko - Moscow Regional Genetics

� Anatoly Skalny - Center for Biotech Medicine, Moscow

� Pavel Ogurtsov -Friendship University, Moscow

I. Spectrum of OutcomesI. Spectrum of Outcomes

– To measure the birth prevalence and range of alcohol-related physical features and neurobehavioral impairment among children born to women who consume moderate to heavy amounts of alcohol in pregnancy relative to children born to mothers who report consuming low amounts or no alcohol during pregnancy

� Three maternal interviews; biomarkers of exposure; banked DNA

� Physical examinations by specially trained neonatologists/geneticists

� Neurobehavioral testing at 6 m and 12 m

– To measure the birth prevalence and range of alcohol-related physical features and neurobehavioral impairment among children born to women who consume moderate to heavy amounts of alcohol in pregnancy relative to children born to mothers who report consuming low amounts or no alcohol during pregnancy

� Three maternal interviews; biomarkers of exposure; banked DNA

� Physical examinations by specially trained neonatologists/geneticists

� Neurobehavioral testing at 6 m and 12 m

II. NutritionII. Nutrition

– To evaluate the contribution of specific micronutrients to risk for various features of FASD

– To conduct a randomized intervention trial of multivitamin supplementation with or without choline supplementation to reduce alcohol-related effects

� Blood samples 2 times in pregnancy

� Random assignment to multivitamin/mineral supplement

� Random assignment to 700 mg choline supplement

– To evaluate the contribution of specific micronutrients to risk for various features of FASD

– To conduct a randomized intervention trial of multivitamin supplementation with or without choline supplementation to reduce alcohol-related effects

� Blood samples 2 times in pregnancy

� Random assignment to multivitamin/mineral supplement

� Random assignment to 700 mg choline supplement

FASD and cholineFASD and choline

� Prenatal choline deficiency leads to long-lasting

hippocampal dysfunction as well as memory and

learning impairments

� In rats, perinatal choline supplementation attenuates the adverse effects of alcohol on hyperactivity and

memory tasks

� complementary sheep and rat models in CIFASD

III. Earlier/Better DiagnosisIII. Earlier/Better Diagnosis

– To test training methods, imaging and

earlier/more sensitive neurobehavioral testing

measures to identify affected infants

� Repeated physical examinations

� Repeated prenatal ultrasound measures

� 2-D and 3-D facial photographs

� Repeated neurobehavioral testing

– To test training methods, imaging and

earlier/more sensitive neurobehavioral testing

measures to identify affected infants

� Repeated physical examinations

� Repeated prenatal ultrasound measures

� 2-D and 3-D facial photographs

� Repeated neurobehavioral testing

Final 3D model constructed from the highest confidence data points.

1.5 Milliseconds

3D - facial imaging3D - facial imaging

3-D facial imaging3-D facial imaging

Preliminary FindingsPreliminary Findings

Maternal interviews - RussiaMaternal interviews - Russia

0.2%Daily drinker most recent month

0.5%Daily drinker month of conception

35.5%Any alcohol most recent month

91.2%Any alcohol month of conception

28.2%Current smokers

13.1 (6.9)Gestational age at enrollment (wks)

25.2 (5.5)Age (years)

Mean (SD) or proportion

Characteristics

N = 1164 Women Interviewed

Any binge episodes - RussiaAny binge episodes - Russia

0

10

20

30

40

50

60

70

80

Perc

en

t o

f E

ver-

Dri

nkers

Rep

ort

ing

at

Least

1 E

pis

od

e

5 or more 4 2 or 3

Number of Drinks per Occasion

Conception

In pregnancy

0

10

20

30

40

50

60

70

80

Perc

en

t o

f E

ver-

Dri

nkers

Rep

ort

ing

at

Least

1 E

pis

od

e

5 or more 4 2 or 3

Number of Drinks per Occasion

Conception

In pregnancy

Number of binge episodesmonth around conception - Russia

Number of binge episodesmonth around conception - Russia

0

5

10

15

20

25

30

Percent of Women

1 to 3 4 to 5 6 or more

Number of Occasions 4 or More Drinks

0

5

10

15

20

25

30

Percent of Women

1 to 3 4 to 5 6 or more

Number of Occasions 4 or More Drinks

Number of drinks can ‘hold’ - RussiaNumber of drinks can ‘hold’ - Russia

0

5

10

15

20

25

30

Perc

en

t o

f W

om

en

1 or 2 3 or 4 5 or 6 7 or 8 9 or more

Number of Drinks on an Occasion

0

5

10

15

20

25

30

Perc

en

t o

f W

om

en

1 or 2 3 or 4 5 or 6 7 or 8 9 or more

Number of Drinks on an Occasion

Signs of abuse in last year - RussiaSigns of abuse in last year - Russia

16.9%

5.0%

23.4%

20.2%

22.6%

17.5%

0

5

10

15

20

25

30

Perc

en

t o

f W

om

en

CAGE TWEAK T-ACE

Number of Points by Screening Test

1 or more

2 or more

16.9%

5.0%

23.4%

20.2%

22.6%

17.5%

0

5

10

15

20

25

30

Perc

en

t o

f W

om

en

CAGE TWEAK T-ACE

Number of Points by Screening Test

1 or more

2 or more

Correspondence of signs of abusefor continued pregnancy drinking - Russia

Correspondence of signs of abusefor continued pregnancy drinking - Russia

<0.0014.45, 14.388.00guilt

0.0081.45, 12.194.21worry

0.660.19, 13.631.63eye opener

<0.0013.15, 15.256.93cut down

0.100.76, 20.593.94annoy

<0.0014.00, 72.1416.98amnesia

p-value95% CI

OR for continued drinking in

pregnancyQuestion

Correlation of maternal binge drinking with paternal drinking - Ukraine

Correlation of maternal binge drinking with paternal drinking - Ukraine

<0.0001

3.55, 20.71

12.20, 124.72

1.0

8.57

39.00

Quantity

1-2 drinks

3-4 drinks

≥5 drinks

<0.0001

4.89, 28.44

8.88, 118.59

1.79, 82.86

1.0

11.80

32.44

12.17

Frequency

<1 x week

1-2 x week

3-4 x week

Daily

p-value95% CI

OR for mother’s binge

drinking

(N = 166)

Partner

drinking

Alcohol related physical features in newborns -Ukraine

Alcohol related physical features in newborns -Ukraine

0.068

0.035

0.118

0.126

1.000

0.032

0.126

0.031

5 (9.1)

2 (3.6)

4 (7.3)

0

3 (5.5)

0

0

0

5 (9.1)

14 (21.2)

10 (15.2)

11 (16.7)

4 (6.0)

4 (6.0)

6 (9.0)

4 (6.0)

3 (4.5)

13 (19.4)

Palpebral fissures ≤10th centile

Smooth philtrum

Thin vermilion border

Hockey stick crease

Birth weight ≤10th centile

Birth length ≤10th centile

Birth head circumference ≤10th centile

FAS

Some features of FAS

p-value

No Alcohol

N = 55

Alcohol

Exposed

N = 67Feature - n (%)

Minerals in Binge-Drinking Women

vs. Unexposed - Russia

Minerals in Binge-Drinking Women

vs. Unexposed - Russia

3rd trimester

N = 20

1st/2nd trimester

N = 20

0.010.780.620.080.730.59Zn

0.150.140.110.170.130.11Se

0.3119.017.80.4919.018.1Mg

0.551.21.00.351.11.4Fe

0.042.62.00.412.42.2Cu

0.1996.888.80.3593.888.5Ca

P-valueAlc-Alc+P-valueAlc-Alc+Mineral

Prenatal ultrasound brain measures - UkrainePrenatal ultrasound brain measures - Ukraine

� Transverse Cerebellar Diameter

� Occipital Frontal Diameter

� Caval-Calvarial Distance

� Frontothalamic Distance

� Outer Orbital Distance

� Interorbital Distance

� Orbital Distance

� Transverse Cerebellar Diameter

� Occipital Frontal Diameter

� Caval-Calvarial Distance

� Frontothalamic Distance

� Outer Orbital Distance

� Interorbital Distance

� Orbital Distance

TCD

T

T

CCD

FTD

TCD

FTD

OODOOD

Fetal growth measures (2nd trimester)

FAS/some features vs. no FAS - Ukraine sample

Fetal growth measures (2nd trimester)

FAS/some features vs. no FAS - Ukraine sample

0.01062.5±2.247.0±5.4Femur length percentile

0.05343.3±3.227.2±7.6Abdominal circumference percentile

0.00641.9±1.828.5±4.4Head circumference percentile

0.23656.1±2.947.0±7.1Biparietal diameter percentile

0.10535.0±1.827.6±4.2Estimated fetal wt percentile

Mean±sdMean±sd

p-valueNo FAS

(n=121)

FAS/D

(n=21)

Fetal Growth Measures*

* All models adjusted for smoking

Fetal growth measures (3rd trimester)

FAS/some features vs. no FAS - Ukraine sample

Fetal growth measures (3rd trimester)

FAS/some features vs. no FAS - Ukraine sample

0.00551.9±3.630.9±6.3Femur length percentile

0.35054.2±3.547.3±6.3Abdominal circumference

percentile

0.00353.8±3.333.9±5.6Head circumference percentile

0.03366.7±4.248.9±7.0Biparietal diameter percentile

0.05433.4±2.324.2±4.0Estimated fetal wt percentile

Mean±sdMean±sd

p-value

No FAS

(n=120)

FAS/D

(n=21)

Fetal Growth Measures*

* All models adjusted for smoking

Fetal brain measures (3rd trimester)

FAS/some features vs. no FAS - Ukraine sample

Fetal brain measures (3rd trimester)

FAS/some features vs. no FAS - Ukraine sample

0.88016.9±0.316.8±0.4Orbital Diameter (mm)

0.30115.6±0.314.9±0.6Interorbital Distance (mm)

0.18055.5±0.654.0±0.9Outer Orbital Diameter (mm)

0.08066.3±0.763.9±1.2Frontothalamic Distance (mm)

0.12743.3±0.641.6±1.0Caval-Calvarial Distance (mm)

0.888107.8±1.5107.4±2.5Occipital Frontal Diameter (mm)

0.17841.9±0.540.8±0.4Transverse Cerebellar Diameter (mm)

Mean±s.e.Mean±s.e.

p-value*

No FAS

(N=120)

FAS/D

(N=21)

Brain Measure

* Adjusted for gestational age & smoking in pregnancy

ConclusionsConclusions

� Accurate diagnoses can be made in the newborn period offering opportunity for early intervention

� Nutritional factors may be important in FASD (and potentially modifiable)

� Prenatal ultrasound may have clinical relevance in identifying alcohol-affected fetuses in mid-gestation

� Accurate diagnoses can be made in the newborn period offering opportunity for early intervention

� Nutritional factors may be important in FASD (and potentially modifiable)

� Prenatal ultrasound may have clinical relevance in identifying alcohol-affected fetuses in mid-gestation

Future plansFuture plans

� Explore better maternal biomarkers

� Link early identification of high risk infants to initiation of early treatment

� Explore better maternal biomarkers

� Link early identification of high risk infants to initiation of early treatment